Hepatic IFNL4 Gene Activation in Hepatocellular Carcinoma Patients with Regard to Etiology.

Henriette Huschka,Sabine Mihm

doi:10.3390/ijms22157803

Abstract

Hepatocellular carcinoma (HCC) is a malignancy with a leading lethality. The etiology is quite diverse, ranging from viral infections to metabolic disorders or intoxications, and associates with specific somatic mutational patterns and specific host immunological phenotypes. Particularly, hepatitis C virus (HCV)-infected liver is featured by an activation of interferon (IFN)-stimulated genes (ISGs; IFN signature), which we suppose is driven by type III IFNL4. Taking advantage of the TCGA collection of HCC patients of various different etiologies, this study aimed at validating our previous findings on hepatic IFNL4 gene activation in HCV infection in an independent and larger cohort of patients with advanced liver disease. In a cohort of n = 377 cases, the entirety of the sequencing data was used to assess the IFNL genotypes, and the cases were stratified for etiology. The number of IFNL4 transcripts within nonmalignant and malignant tissues was found to be more abundant in patients with HCV or HCV/HBV infections when compared to other risk factors. Moreover, in patients with HCV infection as a risk factor, a close, positive relationship was found between ISG activation and the number of functional IFNL4 transcripts. Data on this independent TCGA sample support the concept of an IFNL4-dependent HCV-driven activation of hepatic ISGs. In addition to that, they add to the understanding of etiology-related host immunological phenotypes in HCC.

Highlights

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths [1], with a 5-year survival rate < 20% [2,3]
Beyond etiology-related somatic mutational landscapes and etiology-related acquired immunological phenotypes in HCC, hepatitis C virus (HCV)-infected livers are known to be featured by the activation of interferon (IFN)-stimulated genes (ISGs), which are mediators of the innate immune response
This IFN signature is featured by myxovirus resistance protein A (Mx1), IFN-induced protein 44 (IFI44), and IFN-induced protein with tetratricopeptide repeats 1 (IFIT1) and differs from gene expression profiles in nonviral or metabolic liver disorders and, notably, in hepatitis B virus (HBV) infections in man [10,11,12]

Summary

Introduction

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths [1], with a 5-year survival rate < 20% [2,3]. Beyond etiology-related somatic mutational landscapes and etiology-related acquired immunological phenotypes in HCC, HCV-infected (nonmalignant) livers are known to be featured by the activation of interferon (IFN)-stimulated genes (ISGs), which are mediators of the innate immune response This IFN signature is featured by myxovirus resistance protein A (Mx1), IFN-induced protein 44 (IFI44), and IFN-induced protein with tetratricopeptide repeats 1 (IFIT1) and differs from gene expression profiles in nonviral or metabolic liver disorders and, notably, in HBV infections in man [10,11,12]. Different to other type I or type III IFN genes, IFNL4 harbors a gain- or loss-of-function dinucleotide polymorphism: the phylogenetically older allele ∆G translates into a functional IFN-λ4 protein, while the variant allele TT causes a frameshift disrupting the IFNL4 open reading frame (ORF), thereby abrogating its translation [14] This germline polymorphism is driving the pseudogenization of the IFNL4 gene and, predisposes a subpopulation of human beings only to express a functional

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